Cell Reports (Oct 2017)

Brachyury-YAP Regulatory Axis Drives Stemness and Growth in Cancer

  • Sagar R. Shah,
  • Justin M. David,
  • Nathaniel D. Tippens,
  • Ahmed Mohyeldin,
  • Juan C. Martinez-Gutierrez,
  • Sara Ganaha,
  • Paula Schiapparelli,
  • Duane H. Hamilton,
  • Claudia Palena,
  • Andre Levchenko,
  • Alfredo Quiñones-Hinojosa

Journal volume & issue
Vol. 21, no. 2
pp. 495 – 507

Abstract

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Summary: Molecular factors that define stem cell identity have recently emerged as oncogenic drivers. For instance, brachyury, a key developmental transcriptional factor, is also implicated in carcinogenesis, most notably of chordoma, through mechanisms that remain elusive. Here, we show that brachyury is a crucial regulator of stemness in chordoma and in more common aggressive cancers. Furthermore, this effect of brachyury is mediated by control of synthesis and stability of Yes-associated protein (YAP), a key regulator of tissue growth and homeostasis, providing an unexpected mechanism of control of YAP expression. We further demonstrate that the brachyury-YAP regulatory pathway is associated with tumor aggressiveness. These results elucidate a mechanism of controlling both tumor stemness and aggressiveness through regulatory coupling of two developmental factors. : Malignant neoplasms exhibit uninhibited and dysregulated growth coupled with acquisition of stem-like properties that are integral to the development and progression of disease. Shah et al. demonstrate a critical role of brachyury in regulating stemness and growth by activating YAP through direct transcriptional and post-transcriptional mechanisms in various cancers. Keywords: brachyury, YAP, chordoma, stremness, growth, glioblastoma, lung carcinoma